Pharmaceutical compositions comprising poh derivatives and methods of use

ABSTRACT

The present invention provides for a method of treating a disease such as cancer, comprising the step of administering to a patient a therapeutically effective amount of a perillyl alcohol derivative such as a perillyl alcohol ester, or an isoperillyl alcohol derivative such as an isoperillyl alcohol ester. The derivative may be a perillyl alcohol or an isoperillyl alcohol conjugated with a therapeutic agent such as valproic acid. The route of administration may vary, including inhalation, intranasal, oral, transdermal, intravenous, subcutaneous or intramuscular injection.

FIELD OF THE INVENTION

The present invention relates to perillyl alcohol (POH) derivatives andisoperillyl alcohol (iso-POH) derivatives. The present invention furtherrelates to methods of using perillyl alcohol derivatives (such asperillyl alcohol esters), and isoperillyl alcohol derivatives (such asisoperillyl alcohol esters) to treat cancer.

BACKGROUND OF THE INVENTION

Malignant gliomas, the most common form of central nervous system (CNS)cancers, are currently considered essentially incurable. Among thevarious malignant gliomas, anaplastic astrocytomas (Grade III) andglioblastoma multiforme (GBM; Grade IV) have an especially poorprognosis due to their aggressive growth and resistance to currentlyavailable therapies. The present standard of care for malignant gliomasconsists of surgery, ionizing radiation, and chemotherapy. Despiterecent advances in medicine, the past 50 years have not seen anysignificant improvement in prognosis for malignant gliomas. Wen et al.Malignant gliomas in adults. New England J Med. 359: 492-507, 2008.Stupp et al. Radiotherapy plus concomitant and adjuvant temozolomide forglioblastoma. New England J Med. 352: 987-996, 2005.

The poor response of tumors, including malignant gliomas, to varioustypes of chemotherapeutic agents are often due to intrinsic drugresistance. Additionally, acquired resistance of initiallywell-responding tumors and unwanted side effects are other problems thatfrequently thwart long-term treatment using chemotherapeutic agents.Hence, various analogues of chemotherapeutic agents have been preparedin an effort to overcome these problems. The analogues include noveltherapeutic agents which are hybrid molecules of at least two existingtherapeutic agents. For example, cisplatin has been conjugated withcytotoxic codrugs, or conjugated with bioactive shuttle components suchas porphyrins, bile acids, hormones, or modulators that expedite thetransmembrane transport or the drug accumulation within the cell.(6-Aminomethylnicotinate) dichloridoplatinum (II) complexes esterifiedwith terpene alcohols were tested on a panel of human tumor cell lines.The terpenyl moieties in these complexes appeared to fulfill atransmembrane shuttle function and increased the rate and extent of theuptake of these conjugates into various tumor cell lines. Schobert etal. Monoterpenes as Drug Shuttles: Cytotoxic (6-minomethylnicotinate)dichloridoplatinum(II) Complexes with Potential to Overcome CisplatinResistance. J. Med. Chem. 2007, 50, 1288-1293.

Perillyl alcohol (POH), a naturally occurring monoterpene, has beensuggested to be an effective agent against a variety of cancers,including CNS cancer, breast cancer, pancreatic cancer, lung cancer,melanomas and colon cancer. Gould, M. Cancer chemoprevention and therapyby monoterpenes. Environ Health Perspect. 1997 June; 105 (Suppl 4):977-979. Hybrid molecules containing both perillyl alcohol and retinoidswere prepared to increase apoptosis-inducing activity. Das et al. Designand synthesis of potential new apoptosis agents: hybrid compoundscontaining perillyl alcohol and new constrained retinoids. TetrahedronLetters 2010, 51, 1462-1466.

There is still a need to prepare perillyl alcohol derivatives includingperillyl alcohol conjugated with other therapeutic agents, and use thismaterial in the treatment of cancers such as malignant gliomas, as wellas other brain disorders such as Parkinson's and Alzheimer's disease.There is also a need to prepare isomers or analogs including isoperillylalcohol conjugated with other therapeutic agents, and use this materialin the treatment of various conditions. These compounds may beadministered alone or in combination with other treatment methodsincluding radiation, standard chemotherapy, and surgery. Theadministration can also be through various routes including intranasal,oral, oral-tracheal for puhnonary delivery, and transdermal.

SUMMARY

The present disclosure provides for a pharmaceutical compositioncomprising a perillyl alcohol conjugated with valproic acid. In certainembodiments, the perillyl alcohol conjugated with valproic acid is anester of perillyl alcohol with valproic acid. In one embodiment, theester is 2-Propylpentanoic acid 4-isopropenyl-cyclohex-1-enylmethylester.

The present disclosure also provides for a pharmaceutical compositioncomprising an isoperillyl alcohol conjugated with valproic acid. Incertain embodiments, the isoperillyl alcohol conjugated with valproicacid is an ester of isoperillyl alcohol with valproic acid. In oneembodiment, the ester is 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester.

In certain embodiments, the isoperillyl alcohol is selected from thegroup consisting of (4-isopropylidene cyclohex-1-enyl)methanol,(4-isopropyl cyclohexa-1,3-dienyl)methanol, (4-isopropylcyclohexa-1,4-dienyl)methanol, (4-isopropylphenyl)methanol and(4-isopropenylphenyl)methanol.

The present disclosure provides for a pharmaceutical compositioncomprising a therapeutically effective amount of 2-Propylpentanoic acid4-isopropenyl-cyclohex-1-enylmethyl ester.

Also encompassed by the present disclosure is a pharmaceuticalcomposition comprising a therapeutically effective amount of2-Propyl-pentanoic acid 4-isopropylidene-cyclohex-1-enylmethyl ester.

The present disclosure also provides for a method for treating a diseasein a mammal, comprising the step of administering to the mammal atherapeutically effective amount of a perillyl alcohol conjugated withvalproic acid. In certain embodiments, the perillyl alcohol conjugatedwith valproic acid is an ester of perillyl alcohol with valproic acid.In one embodiment, the ester is 2-Propylpentanoic acid4-isopropenyl-cyclohex-1-enylmethyl ester.

The present disclosure provides for a method for treating a disease in amammal, comprising the step of administering to the mammal atherapeutically effective amount of an isoperillyl alcohol conjugatedwith valproic acid. In certain embodiments, the isoperillyl alcoholconjugated with valproic acid is an ester of isoperillyl alcohol withvalproic acid. In one embodiment, the ester is 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester.

In certain embodiments, the disease is cancer. In certain embodiments,the cancer is a tumor of the nervous system. In certain embodiments, thetumor is a glioblastoma.

In certain embodiments, the present method further comprises the step oftreating the mammal with radiation. In certain embodiments, the presentmethod further comprises the step of administering to the mammal achemotherapeutic agent.

The present pharmaceutical composition or agent may be administered byinhalation, intranasally, orally, intravenously, subcutaneously orintramuscularly.

In certain embodiments, the pharmaceutical composition or agent isadmixed or coformulated with a therapeutic agent.

The present disclosure provides for a method for treating a disease in amammal, comprising the step of administering to the mammal atherapeutically effective amount of a perillyl alcohol conjugated withvalproic acid or an isoperillyl alcohol conjugated with valproic acidusing a nasal delivery device. In certain embodiments, the nasaldelivery device is selected from the group consisting of an intranasalinhaler, an intranasal spray device, an atomizer, a nebulizer, a metereddose inhaler (MDI), a pressurized dose inhaler, an insufflator, a unitdose container, a pump, a dropper, a squeeze bottle and a bi-directionaldevice.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides for derivatives of monoterpene orsesquiterpene, such as perillyl alcohol derivatives. The presentdisclosure also provides for a pharmaceutical composition comprising aderivative of monoterpene or sesquiterpene, such as a perillyl alcoholderivative. For example, the perillyl alcohol derivative may be aperillyl alcohol ester. The perillyl alcohol ester may be perillylalcohol conjugated with valproic acid (or valproate).

The present disclosure provides for derivatives of isomers or analogs ofmonoterpene or sesquiterpene, such as isoperillyl alcohol derivatives.The present disclosure also provides for a pharmaceutical compositioncomprising a derivative of isomers or analogs of monoterpene orsesquiterpene, such as an isoperillyl alcohol derivative. For example,the isoperillyl alcohol derivative may be an isoperillyl alcohol ester.The isoperillyl alcohol ester may be isoperillyl alcohol conjugated withvalproic acid (or valproate).

The present compounds can be administered alone, or may beco-administered together with radiation or another agent (e.g., achemotherapeutic agent), to treat a disease such as cancer. Treatmentsmay be sequential, with the present compounds being administered beforeor after the administration of other agents. For example, a perillylalcohol ester (or an isoperillyl alcohol ester) may be used to sensitizea cancer patient to radiation or chemotherapy. Alternatively, agents maybe administered concurrently. The route of administration may vary, andcan include, inhalation, intranasal, oral, transdermal, intravenous,subcutaneous or intramuscular injection. The present invention alsoprovides for a method of treating a disease such as cancer, comprisingthe step of delivering to a patient a therapeutically effective amountof a derivative of monoterpene (or sesquiterpene), or a derivative ofisomers or analogs of monoterpene or sesquiterpene.

The present compositions may contain a derivative of monoterpene orsesquiterpene, and/or a derivative of isomers or analogs of monoterpeneor sesquiterpene.

The derivatives of monoterpene (or sesquiterpene) include, but are notlimited to, esters, carbamates, ethers, alcohols and aldehydes of themonoterpene (or sesquiterpene). Monoterpene (or sesquiterpene) alcoholsmay be derivatized to esters, carbamates, ethers, aldehydes or acids.

A specific example of a monoterpene is perillyl alcohol (commonlyabbreviated as POH). The derivatives of perillyl alcohol include,perillyl alcohol esters, perillyl alcohol carbamates, perillicaldehydes, dihydroperillic acid, perillic acid, perillic aldehydederivatives, dihydroperillic acid esters and perillic acid esters. Thederivatives of perillyl alcohol may also include its oxidative andnucleophilic/electrophilic addition derivatives. U.S. Patent PublicationNo. 20090031455. U.S. Pat. Nos. 6,133,324 and 3,957,856.

The present disclosure provides for a derivative of a monoterpene orsesquiterpene, such as a perillyl alcohol derivative. For example, theperillyl alcohol derivative may be perillyl alcohol ester, carbamate, orether. The derivative of a monoterpene or sesquiterpene may be amonoterpene or sesquiterpene conjugated with a therapeutic agent such asvalproic acid (or valproate). The perillyl alcohol derivative may beperillyl alcohol conjugated with a therapeutic agent such as valproicacid (or valproate).

Monoterpenes include terpenes that consist of two isoprene units.Monoterpenes may be linear (acyclic) or contain rings. Derivatives ofmonoterpenoids are also encompassed by the present invention.Monoterpenoids may be produced by biochemical modifications such asoxidation or rearrangement of monoterpenes. Examples of monoterpenes andmonoterpenoids include, perillyl alcohol (S(−)) and (R(+)), ocimene,myrcene, geraniol, citral, citronellol, citronellal, linalool, pinene,terpineol, terpinen, limonene, terpinenes, phellandrenes, terpinolene,terpinen-4-ol (or tea tree oil), pinene, terpineol, terpinen; theterpenoids such as p-cymene which is derived from monocyclic terpenessuch as menthol, thymol and carvacrol; bicyclic monoterpenoids such ascamphor, borneol and eucalyptol.

Monoterpenes may be distinguished by the structure of a carbon skeletonand may be grouped into acyclic monoterpenes (e.g., myrcene, (Z)- and(E)-ocimene, linalool, geraniol, nerol, citronellol, myrcenol, geranial,citral a, neral, citral b, citronellal, etc.), monocyclic monoterpenes(e.g., limonene, terpinene, phellandrene, terpinolene, menthol, carveol,etc.), bicyclic monoterpenes (e.g., pinene, myrtenol, myrtenal,verbanol, verbanon, pinocarveol, carene, sabinene, camphene, thujene,etc.) and tricyclic monoterpenes (e.g. tricyclene). See Encyclopedia ofChemical Technology, Fourth Edition, Volume 23, page 834-835.

Sesquiterpenes include terpenes that consist of three isoprene units.Sesquiterpenes may be linear (acyclic) or contain rings. Derivatives ofsesquiterpenoids are also encompassed by the present invention.Sesquiterpenoids may be produced by biochemical modifications such asoxidation or rearrangement of sesquiterpenes. Examples of sesquiterpenesinclude farnesol, farnesal, farnesylic acid and nerolidol. U.S.Provisional Application Nos. 61/310,231 (filed on Mar. 3, 2010),61/377,747 (filed on Aug. 27, 2010), 61/471,402 (filed on Apr. 4, 2011)and 61/562,105 (filed on Nov. 21, 2011). PCT Application Nos.PCT/US2011/027051 (filed on Mar. 3, 2011) and PCT/US2011/049392 (filedon Aug. 26, 2011). U.S. application Ser. No. 13/040,059 (filed on Mar.3, 2011). All these applications are incorporated herein by reference intheir entirety.

The derivatives of isomers or analogs of monoterpene or sesquiterpeneinclude, but are not limited to, esters, carbamates, ethers, alcoholsand aldehydes of the isomers or analogs of monoterpene or sesquiterpene.Alcohols may be derivatized to esters, carbamates, ethers, aldehydes oracids.

The isomer or analog of monoterpene or sesquiterpene can be anisoperillyl alcohol (iso-POH). Isoperillyl alcohols include any isomersor analogs of perillyl alcohol. In one embodiment, the isoperillylalcohol is (4-isopropylidene cyclohex-1-enyl)methanol. Other examples ofisoperillyl alcohol include, but are not limited to, (4-isopropylcyclohexa-1,3-dienyl)methanol, (4-isopropylcyclohexa-1,4-dienyl)methanol, (4-isopropylphenyl)methanol and(4-isopropenylphenyl)methanol. An exemplary isoperillyl alcohol,(4-isopropylidene cyclohex-1-enyl)methanol, is shown below:

Also encompassed by the present invention is a derivative of an isomeror analog of monoterpene or sesquiterpene, such as an isoperillylalcohol derivative. For example, the isoperillyl alcohol derivative maybe an isoperillyl alcohol ester, carbamate, or ether. The derivative ofan isomer or analog of monoterpene or sesquiterpene may be an isomer oranalog of monoterpene or sesquiterpene conjugated with a therapeuticagent such as valproic acid (or valproate). The isoperillyl alcoholderivative may be isoperillyl alcohol conjugated with a therapeuticagent such as valproic acid (or valproate). The derivatives ofisoperillyl alcohol include isoperillyl alcohol esters, isoperillylalcohol carbamates, isoperillic aldehydes, isoperillic acid, isoperillicaldehyde derivatives, and isoperillic acid esters. The derivatives ofisoperillyl alcohol may also include its oxidative andnucleophilic/electrophilic addition derivatives. U.S. Pat. No.5,994,598.

Esters of the monoterpene (or sesquiterpene) alcohols of the presentinvention can be derived from an inorganic acid or an organic acid.Esters of the alcohols of the isomers or analogs of monoterpene orsesquiterpene can be derived from an inorganic acid or an organic acid.Inorganic acids include, but are not limited to, phosphoric acid,sulfuric acid, and nitric acid. Organic acids include, but are notlimited to, carboxylic acid such as valproic acid, benzoic acid, fattyacid, acetic acid and propionic acid, and any therapeutic agent bearingat least one carboxylic acid functional group. Examples of the esters ofalcohols include, but are not limited to, carboxylic acid esters (suchas valproic acid esters, benzoate esters, fatty acid esters (e.g.,palmitate ester, linoleate ester, stearate ester, butyryl ester andoleate ester), acetates, propionates (or propanoates), and formates),phosphates, sulfates, and carbamates (e.g., N,N-dimethylaminocarbonyl).

In certain embodiments, the perillyl alcohol derivative is perillylalcohol conjugated with valproic acid (or valproate). In one embodiment,the POH-valproate conjugate is 2-Propylpentanoic acid4-isopropenyl-cyclohex-1-enylmethyl ester with the following structure:

In certain embodiments, the isoperillyl alcohol derivative isisoperillyl alcohol conjugated with valproic acid (or valproate). In oneembodiment, the iso-POH-valproate conjugate is 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester with the followingstructure:

Carbamate refers to a class of chemical compounds sharing the functionalgroup

based on a carbonyl group flanked by an oxygen and a nitrogen. R¹, R²and R can be a group such as alkyl, aryl, etc., which can besubstituted. The R groups on the nitrogen and the oxygen may form aring. R¹—OH may be a monoterpene, e.g., POH, or isomers or analogs ofmonoterpene or sesquiterpene, e.g., iso-POH. The R²—N—R³ moiety may be atherapeutic agent.

Carbamates may be synthesized by reacting isocyanate and alcohol, or byreacting chloroformate with amine. Carbamates may be synthesized byreactions making use of phosgene or phosgene equivalents. For example,carbamates may be synthesized by reacting phosgene gas, diphosgene or asolid phosgene precursor such as triphosgene with two amines or an amineand an alcohol. Carbamates (also known as urethanes) can also be madefrom reaction of a urea intermediate with an alcohol. Dimethyl carbonateand diphenyl carbonate are also used for making carbamates.Alternatively, carbamates may be synthesized through the reaction ofalcohol and/or amine precursors with an ester-substituted diarylcarbonate, such as bismethylsalicylcarbonate (BMSC). U.S. PatentPublication No. 20100113819.

Carbamates may be synthesized by the following approach:

Suitable reaction solvents include, but are not limited to,tetrahydrofuran, dichloromethane, dichloroethane, acetone, anddiisopropyl ether. The reaction may be performed at a temperatureranging from about −70° C. to about 80° C., or from about −65° C. toabout 50° C. The molar ratio of perillyl chloroformate (or isoperillylchloroformate) to the substrate R—NH₂ may range from about 1:1 to about2:1, from about 1:1 to about 1.5:1, from about 2:1 to about 1:1, or fromabout 1.05:1 to about 1.1:1. Suitable bases include, but are not limitedto, organic bases, such as triethylamine, potassium carbonate,N,N′-diisopropylethylamine, butyl lithium, and potassium-t-butoxide.

Alternatively, carbanmates may be synthesized by the following approach:

Suitable reaction solvents include, but are not limited to,dichloromethane, dichloroethane, toluene, diisopropyl ether, andtetrahydrofuran. The reaction may be performed at a temperature rangingfrom about 25° C. to about 110° C., or from about 30° C. to about 80°C., or about 50° C. The molar ratio of perillyl alcohol (or isoperillylalcohol) to the substrate R—N═C═O may range from about 1:1 to about 2:1,from about 1:1 to about 1.5:1, from about 2:1 to about 1:1, or fromabout 1.05:1 to about 1.1:1.

In certain embodiments, a POH carbamate is synthesized by a processcomprising the step of reacting a first reactant of perillylchloroformate with a second reactant such as dimethyl celocoxib (DMC),temozolomide (TMZ) and rolipram. The reaction may be carried out in thepresence of tetrahydrofuran and a base such as n-butyl lithium. Perillylchloroformate may be made by reacting POH with phosgene. For example,POH conjugated with temozolomide through a carbamate bond may besynthesized by reacting temozolomide with oxalyl chloride followed byreaction with perillyl alcohol. The reaction may be carried out in thepresence of 1,2-dichloroethane.

POH carbamates encompassed by the present invention include, but notlimited to, 4-(bis-N,N′-4-isopropenyl cyclohex-1-enylmethyloxy carbonyl[5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl]benzenesulfonamide, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenylcyclohex-1-enylmethyl ester, and (3-methyl4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)carbamicacid-4-isopropenyl cyclohex-1-enylmethyl ester.

In certain embodiments, an iso-POH carbamate is synthesized by a processcomprising the step of reacting a first reactant of isoperillylchloroformate with a second reactant such as dimethyl celocoxib (DMC),temozolomide (TMZ) and rolipram. The reaction may be carried out in thepresence of tetrahydrofuran and a base such as n-butyl lithium.Isoperillyl chloroformate may be made by reacting iso-POH with phosgene.For example, iso-POH conjugated with temozolomide through a carbamatebond may be synthesized by reacting temozolomide with oxalyl chloridefollowed by reaction with isoperillyl alcohol. The reaction may becarried out in the presence of 1,2-dichloroethane.

Iso-POH carbamates encompassed by the present invention include, but arenot limited to, (3-Methyl4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamicacid-4-isopropylidene cyclohex-1-enylmethyl ester,4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid4-isopropylidene cyclohex-1-enylmethyl ester,4-(Bis-N,N′-4-isopropylidene cyclohex-1-enylmethyloxy carbonyl[5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl]benzenesulfonamide.

In certain embodiments, iso-perillyl alcohol derivatives may beisoperillyl alcohol fatty acid esters, such as palmitoyl ester ofiso-POH and linoleoyl ester of iso-POH.

The monoterpene (or sesquiterpene) derivative may be a monoterpene (orsesquiterpene) conjugated with a therapeutic agent. A monoterpene (orsesquiterpene) conjugate encompassed by the present invention is amolecule having a monoterpene (or sesquiterpene) covalently bound via achemical linking group to a therapeutic agent. The molar ratio of themonoterpene (or sesquiterpene) to the therapeutic agent in themonoterpene (or sesquiterpene) conjugate may be 1:1, 1:2, 1:3, 1:4, 2:1,3:1, 4:1, or any other suitable molar ratios. The monoterpene (orsesquiterpene) and the therapeutic agent may be covalently linkedthrough carbamate, ester, ether bonds, or any other suitable chemicalfunctional groups. When the monoterpene (or sesquiterpene) and thetherapeutic agent are conjugated through a carbamate bond, thetherapeutic agent may be any agent bearing at least one carboxylic acidfunctional group, or any agent bearing at least one amine functionalgroup. In a specific example, a perillyl alcohol conjugate is perillylalcohol covalently bound via a chemical linking group to achemotherapeutic agent.

The present invention provides for methods of treating a disease such ascancer using a derivative of perillyl alcohol or a derivative of anisoperillyl alcohol. Routes of administration include inhalation,intranasal, oral, transdermal, intravenous, subcutaneous andintramuscular injection.

In the present methods, a patient is administered a therapeuticallyeffective amount of a derivative of perillyl alcohol or a derivative ofan isoperillyl alcohol. The present invention also provides for a methodof treating a disease comprising the step of administering to a patienta therapeutically effective amount of a derivative of monoterpene orsesquiterpene, such as an perillyl alcohol ester. The derivative may beperillyl alcohol conjugated with a therapeutic agent such as valproicacid. The present invention also provides for a method of treating adisease comprising the step of administering to a patient atherapeutically effective amount of a derivative of an isomer or analogof monoterpene or sesquiterpene, such as an isoperillyl alcohol ester.The derivative may be an isoperillyl alcohol conjugated with atherapeutic agent such as valproic acid.

The present compounds may be used for the treatment of nervous systemcancers, such as a malignant glioma (e.g., astrocytoma, anaplasticastrocytoma, glioblastoma muhiforme), retinoblastoma, pilocyticastrocytomas (grade 1), meningiomas, metastatic brain tumors,neuroblastoma, pituitary adenomas, skull base meningiomas, and skullbase cancer. The present invention also provides methods of treating CNS(central nervous system) disorders, including, without limitation,primary degenerative neurological disorders such as Alzheimer's,Parkinson's, psychological disorders, psychosis and depression.

The present compound may be formulated into a pharmaceuticalcomposition, where the present compound is present in amounts rangingfrom about 0.01% (w/w) to about 100% (w/w), from about 0.1% (w/w) toabout 80% (w/w), from about 1% (w/w) to about 70% (w/w), from about 10%(w/w) to about 60% (w/w), or from about 0.1% (w/w) to about 20% (w/w).The present compositions can be administered alone, or may beco-administered together with radiation or another agent (e.g., achemotherapeutic agent), to treat a disease such as cancer. Treatmentsmay be sequential, with the present compounds/compositions beingadministered before or after the administration of other agents. Forexample, a perillyl alcohol derivative (and/or an isoperillyl alcoholderivative) may be used to sensitize a cancer patient to radiation orchemotherapy. Alternatively, agents may be administered concurrently.The route of administration may vary, and can include, inhalation,intranasal, oral, transdermal, intravenous, subcutaneous orintramuscular injection.

The derivative of a monoterpene or sesquiterpene may be a monoterpene orsesquiterpene conjugated with a therapeutic agent. The derivative of anisomer or analog of monoterpene or sesquiterpene may be an isomer oranalog of monoterpene or sesquiterpene conjugated with a therapeuticagent. A conjugate encompassed by the present invention is a moleculehaving a monoterpene or sesquiterpene (or an isomer or analog ofmonoterpene or sesquiterpene) covalently bound via a chemical linkinggroup to a therapeutic agent. The molar ratio of the monoterpene orsesquiterpene (or an isomer or analog of monoterpene or sesquiterpene)to the therapeutic agent in the conjugate may be 1:1, 1:2, 1:3, 1:4,2:1, 3:1, 4:1, or any other suitable molar ratios. The monoterpene orsesquiterpene and the therapeutic agent may be covalently linked throughester, carbamate, ether bonds, or any other suitable chemical functionalgroups. The isomer or analog of monoterpene or sesquiterpene and thetherapeutic agent may be covalently linked through ester, carbamate,ether bonds, or any other suitable chemical functional groups.

The therapeutic agents that may be conjugated with a monoterpene orsesquiterpene (or an isomer or analog of monoterpene or sesquiterpene)include, but are not limited to, chemotherapeutic agents, therapeuticagents for treatment of CNS disorders (including, without limitation,primary degenerative neurological disorders such as Alzheimer's,Parkinson's, multiple sclerosis, Attention-Deficit HyperactivityDisorder or ADHD, psychological disorders, psychosis and depression),immunotherapeutic agents, angiogenesis inhibitors, and anti-hypertensiveagents. Anti-cancer agents that may be conjugated with a monoterpene orsesquiterpene (or an isomer or analog of monoterpene or sesquiterpene)can have one or more of the following effects on cancer cells or thesubject: cell death; decreased cell proliferation; decreased numbers ofcells; inhibition of cell growth; apoptosis; necrosis; mitoticcatastrophe; cell cycle arrest; decreased cell size; decreased celldivision; decreased cell survival; decreased cell metabolism; markers ofcell damage or cytotoxicity; indirect indicators of cell damage orcytotoxicity such as tumor shrinkage; improved survival of a subject; ordisappearance of markers associated with undesirable, unwanted, oraberrant cell proliferation. U.S. Patent Publication No. 20080275057.

Also encompassed by the present invention are admixtures and/orcoformulations of the present compound and at least one othertherapeutic agent.

Chemotherapeutic agents include, but are not limited to, DNA alkylatingagents, topoisomerase inhibitors, endoplasmic reticulum stress inducingagents, a platinum compound, an antimetabolite, vincalkaloids, taxanes,epothilones, enzyme inhibitors, receptor antagonists, tyrosine kinaseinhibitors, boron radiosensitizers (i.e. velcade), and chemotherapeuticcombination therapies.

Non-limiting examples of DNA alkylating agents are nitrogen mustards,such as Cyclophosphamide (Ifosfamide, Trofosfamide), Chlorambucil(Melphalan, Prednimustine), Bendamustine, Uramustine and Estramustine;nitrosoureas, such as Carmustine (BCNU), Lomustine (Semustine),Fotemustine, Nimustine, Ranimustine and Streptozocin; alkyl sulfonates,such as Busulfan (Mannosulfan, Treosulfan); Aziridines, such asCarboquone, Triaziquone, Triethylenemelamine; Hydrazines (Procarbazine);Triazenes such as Dacarbazine and Temozolomide; Altretamine andMitobronitol.

Non-limiting examples of Topoisomerase I inhibitors include Campothecinderivatives including SN-38, APC, NPC, campothecin, topotecan, exatecanmesylate, 9-nitrocamptothecin, 9-aminocamptothecin, lurtotecan,rubitecan, silatecan, gimatecan, diflomotecan, extatecan, BN-80927,DX-8951 f, and MAG-CPT as described in Pommier Y. (2006) Nat. Rev.Cancer 6(10):789-802 and U.S. Patent Publication No. 200510250854;Protoberberine alkaloids and derivatives thereof including berberrubineand coralyne as described in Li et al. (2000) Bichemistry39(24):7107-7116 and Gatto et al. (1996) Cancer Res. 15(12):2795-2800;Phenanthroline derivatives including Benzo[i]phenanthridine, Nitidine,and fagaronine as described in Makhey et al. (2003) Bioorg. Med. Chem.11 (8): 1809-1820; Terbenzimidazole and derivatives thereof as describedin Xu (1998) Biochemistry 37(10):3558-3566; and Anthracyclinederivatives including Doxorubicin, Daunorubicin, and Mitoxantrone asdescribed in Foglesong et al. (1992) Cancer Chemother. Pharmacol.30(2):123-]25, Crow et al. (1994) J. Med. Chem. 37(19):31913194, andCrespi et al. (1986) Biochem. Biophys. Res. Commun. 136(2):521-8.Topoisomerase II inhibitors include, but are not limited to Etoposideand Teniposide. Dual topoisomerase I and II inhibitors include, but arenot limited to, Saintopin and other Naphthecenediones, DACA and otherAcridine-4-Carboxamindes, Intoplicine and other Benzopyridoindoles,TAS-103 and other 7H-indeno[2,1-c]Quinoline-7-ones, Pyrazoloacridine, XR11576 and other Benzophenazines, XR 5944 and other Dimeric compounds,7-oxo-7H-dibenz[f,ij]lsoquinolines and 7-oxo-7H-benzo[e]pyrimidines, andAnthracenyl-amino Acid Conjugates as described in Denny and Baguley(2003) Curr. Top. Med. Chem. 3(3):339-353. Some agents inhibitTopoisomerase II and have DNA intercalation activity such as, but notlimited to, Anthracyclines (Aclarubicin, Daunorubicin, Doxorubicin,Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin)and Antracenediones (Mitoxantrone and Pixantrone).

Examples of endoplasmic reticulum stress inducing agents include, butare not limited to, dimethyl-celecoxib (DMC), nelfinavir, celecoxib, andboron radiosensitizers (i.e. velcade (Bortezomib)).

Platinum based compounds are a subclass of DNA alkylating agents.Non-limiting examples of such agents include Cisplatin, Nedaplatin,Oxaliplatin, Triplatin tetranitrate, Satraplatin, Aroplatin, Lobaplatin,and JM-216. (see McKeage et al. (1997) J. Clin. Oncol. 201:1232-1237 andin general, CHEMOTHERAPY FOR GYNECOLOGICAL NEOPLASM, CURRENT THERAPY ANDNOVEL APPROACHES, in the Series Basic and Clinical Oncology, Angioli etal. Eds., 2004).

“FOLFOX” is an abbreviation for a type of combination therapy that isused to treat colorectal cancer. It includes 5-FU, oxaliplatin andleucovorin. Information regarding this treatment is available on theNational Cancer Institute's web site, cancer.gov, last accessed on Jan.16, 2008.

“FOLFOX/BV” is an abbreviation for a type of combination therapy that isused to treat colorectal cancer. This therapy includes 5-FU,oxaliplatin, leucovorin and Bevacizumab. Furthermore, “XELOX/BV” isanother combination therapy used to treat colorectal cancer, whichincludes the prodrug to 5-FU, known as Capecitabine (Xeloda) incombination with oxaliplatin and bevacizumab. Infonnation regardingthese treatments are available on the National Cancer Institute's website, cancer.gov or from 23 the National Comprehensive Cancer Network'sweb site, nccn.org, last accessed on May 27, 2008.

Non-limiting examples of antimetabolite agents include Folic acid based,i.e. dihydrofolate reductase inhibitors, such as Aminopterin,Methotrexate and Pemetrexed; thymidylate synthase inhibitors, such asRaltitrexed, Pemetrexed; Purine based, i.e. an adenosine deaminaseinhibitor, such as Pentostatin, a thiopurine, such as Thioguanine andMercaptopurine, a halogenated/ribonucleotide reductase inhibitor, suchas Cladribine, Clofarabine, Fludarabine, or a guanine/guanosine:thiopurine, such as Thioguanine; or Pyrimidine based, i.e.cytosine/cytidine: hypomethylating agent, such as Azacitidine andDecitabine, a DNA polymerase inhibitor, such as Cytarabine, aribonucleotide reductase inhibitor, such as Gemcitabine, or athymine/thymidine: thymidylate synthase inhibitor, such as aFluorouracil (5-FU). Equivalents to 5-FU include prodrugs, analogs andderivative thereof such as 5′-deoxy-5-fluorouridine (doxifluroidine),l-tetrahydrofuranyl-5-fluorouracil (foratfur), Capecitabine (Xeloda),S-I (MBMS-247616, consisting of tegafor and two modulators, a5-chloro-2,4-dihydroxypyridine and potassium oxonate), ralititrexed(tomudex), nolatrexed (Thymitaq, AG337), LY231514 and ZD9331, asdescribed for example in Papamicheal (1999) The Oncologist 4:478-487.

Examples of vincalkaloids, include, but are not limited to Vinblastine,Vincristine, Vinflunine, Vindesine and Vinorelbine.

Examples of taxanes include, but are not limited to docetaxel,Larotaxel, Ortataxel, Paclitaxel and Tesetaxel. An example of anepothilone is iabepilone.

Examples of enzyme inhibitors include, but are not limited tofarnesyltransferase inhibitors (Tipifarnib); CDK inhibitor (Alvocidib,Seliciclib); proteasome inhibitor (Bortezomib); phosphodiesteraseinhibitor (Anagrelide; rolipram); IMP dehydrogenase inhibitor(Tiazofurine); and lipoxygenase inhibitor (Masoprocol). Examples ofreceptor antagonists include, but are not limited to ERA (Atrasentan);retinoid X receptor (Bexarotene); and a sex steroid (Testolactone).

Examples of tyrosine kinase inhibitors include, but are not limited toinhibitors to ErbB: HER1/EGFR (Erlotinib, Gefitinib, Lapatinib,Vandetanib, Sunitinib, Neratinib); HER2/neu (Lapatinib, Neratinib); RTKclass ill: C-kit (Axitinib, Sunitinib, Sorafenib), FLT3 (Lestaurtinib),PDGFR (Axitinib, Sunitinib, Sorafenib); and VEGFR (Vandetanib,Semaxanib, Cediranib, Axitinib, Sorafenib); bcr-abl (Imatinib,Nilotinib, Dasatinib); Src (Bosutinib) and Janus kinase 2(Lestaurtinib).

“Lapatinib” (Tykerb®) is a dual EGFR and erbB-2 inhibitor. Lapatinib hasbeen investigated as an anticancer monotherapy, as well as incombination with trastuzumab, capecitabine, letrozole, paclitaxel andFOLFIRI (irinotecan, 5-fluorouracil and leucovorin), in a number ofclinical trials. It is currently in phase Ill testing for the oraltreatment of metastatic breast, head and neck, lung, gastric, renal andbladder cancer.

A chemical equivalent of lapatinib is a small molecule or compound thatis a tyrosine kinase inhibitor (TKI) or alternatively a HER-1 inhibitoror a HER-2 inhibitor. Several TKIs have been found to have effectiveantitumor activity and have been approved or are in clinical trials.Examples of such include, but are not limited to, Zactima (ZD6474),Iressa (gefitinib), imatinib mesylate (STI 571; Gleevec), erlotinib(OSI-1774; Tarceva), canertinib (CI 1033), semaxinib (SU5416), vatalanib(PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SUI 1248) andlefltmomide (SU101).

PTK/ZK is a tyrosine kinase inhibitor with broad specificity thattargets all VEGF receptors (VEGFR), the platelet-derived growth factor(PDGF) receptor, c-KIT and c-Fms. Drevs (2003) Idrugs 6(8):787-794.PTK/ZK is a targeted drug that blocks angiogenesis and lymphangiogenesisby inhibiting the activity of all known receptors that bind VEGFincluding VEGFR-1 (Fit-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4). Thechemical names of PTK/ZK are 1-[4-Chloroanilino]-4-[4-pyridylmethyl]phthalazine Succinate or 1-Phthalazinamine,N-(4-chlorophenyl)-4-(4-pyridinylmethyl)-butanedioate (1:1). Synonymsand analogs of PTK/TK are known as Vatalanib, CGP79787D, PTK787/ZK222584, CGP-79787, DE-00268, PTK-787, PTK787A, VEGFR-TK inhibitor, ZK222584 and ZK.

Chemotherapeutic agents that can be used in admixtures and/orcoformulations, and/or conjugated with a monoterpene or sesquiterpene,and/or conjugated with an isomer or analog of monoterpene orsesquiterpene may also include amsacrine, Trabectedin, retinoids(Alitretinoin, Tretinoin), Arsenic trioxide, asparagine depleterAsparaginase/i Pegaspargase), Celecoxib, Demecolcine, Elesclomol,Elsamitrucin, Etoglucid, Lonidamine, Lucanthone, Mitoguazone, Mitotane,Oblimersen, Temsirolimus, and Vorinostat.

A monoterpene or sesquiterpene, or an isomer or analog of monoterpene orsesquiterpene, may be conjugated and/or used in admixtures and/orcoformulations with angiogenesis inhibitors. Examples of angiogenesisinhibitors include, but are not limited to, angiostatin, angiozyme,antithrombin III, AG3340, VEGF inhibitors, batimastat, bevacizumab(avastin), BMS-275291, CAI, 2C3, HuMV833 Canstatin, Captopril,carboxyamidotriazole, cartilage derived inhibitor (CDI), CC-5013,6-O-(chloroacetyl-carbonyl)-fumagillol, COL-3, combretastatin,combretastatin A4 Phosphate, Dalteparin, EMD 121974 (Cilengitide),endostatin, erlotinib, gefitinib (Iressa), genistein, halofuginonehydrobromide, Id1, Id3, IM862, imatinib mesylate, IMC-IC11 Inducibleprotein 10, interferon-alpha, interleukin 12, lavendustin A, LY317615 orAE-941, marimastat, mspin, medroxpregesterone acetate, Meth-1, Meth-2,2-methoxyestradiol (2-ME), neovastat, oteopontin cleaved product, PEX,pigment epithelium growth factor (PEGF), platelet factor 4, prolactinfragment, proliferin-related protein (PRP), PTK787/ZK 222584, ZD6474,recombinant human platelet factor 4 (rPF4), restin, squalamine, SU5416,SU6668, SU11248 suramin, Taxol, Tecogalan, thalidomide, thrombospondin,TNP-470, troponin-1, vasostatin, VEGI, VEGF-Trap, and ZD6474.

Non-limiting examples of angiogenesis inhibitors also include, tyrosinekinase inhibitors, such as inhibitors of the tyrosine kinase receptorsFlt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived,fibroblast-derived, or platelet derived growth factors, MMP (matrixmetalloprotease) inhibitors, integrin blockers, pentosan polysulfate,angiotensin II antagonists, cyclooxygenase inhibitors (includingnon-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin andibuprofen, as well as selective cyclooxygenase-2 inhibitors such ascelecoxib and rofecoxib), and steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be conjugated and/or admixed and/or coformulated with a monoterpeneor sesquiterpene (or an isomer or analog of monoterpene orsesquiterpene) include agents that modulate or inhibit the coagulationand fibrinolysis systems, including, but not limited to, heparin, lowmolecular weight heparins and carboxypeptidase U inhibitors (also knownas inhibitors of active thrombin activatable fibrinolysis inhibitor[TAFIa]). U.S. Patent Publication No. 20090328239. U.S. Pat. No.7,638,549.

Non-limiting examples of the anti-hypertensive agents includeangiotensin converting enzyme inhibitors (e.g., captopril, enalapril,delapril etc.), angiotensin II antagonists (e.g., candesartan cilexetil,candesartan, losartan (or Cozaar), losartan potassium, eprosartan,valsartan (or Diovan), termisartan, irbesartan, tasosartan, olmesartan,olmesartan medoxomil etc.), calcium antagonists (e.g., manidipine,nifedipine, amlodipine (or Amlodin), efonidipine, nicardipine etc.),diuretics, renin inhibitor (e.g., aliskiren etc.), aldosteroneantagonists (e.g., spironolactone, eplerenone etc.), beta-blockers(e.g., metoprolol (or Toporol), atenolol, propranolol, carvedilol,pindolol etc.), vasodilators (e.g., nitrate, soluble guanylate cyclasestimulator or activator, prostacycline etc.), angiotensin vaccine,clonidine and the like. U.S. Patent Publication No. 20100113780.

Other therapeutic agents that may be conjugated, and/or admixed and/orcoformulated, with monoterpene (or sesquiterpene), or with an isomer oranalog of monoterpene or sesquiterpene, include, but are not limited to,Sertraline (Zoloft), Topiramate (Topamax), Duloxetine(Cymbalta),Sumatriptan (Imitrex), Pregabalin (Lyrica), Lamotrigine (Lamictal),Valaciclovir (Valtrex), Tamsulosin (Flomax), Zidovudine (Combivir),Lamivudine (Combivir), Efavirenz (Sustiva), Abacavir (Epzicom),Lopinavir (Kaletra), Pioglitazone (Actos), Desloratidine (Clarinex),Cetirizine (Zyrtec), Pentoprazole (Protonix), Lansoprazole (Prevacid),Rebeprazole (Aciphex), Moxifloxacin (Avelox), Meloxicam (Mobic),Dorzolamide (Truspot), Diclofenac (Voltaren), Enlapril (Vasotec),Montelukast (Singulair), Sildenafil (Viagra), Carvedilol (Coreg),Ramipril (Delix).

Table 1 lists pharmaceutical agents that can be conjugated with amonoterpene (or sesquiterpene), or with an isomer or analog ofmonoterpene or sesquiterpene, including the structure of thepharmaceutical agent and the preferred derivative for conjugation.

TABLE 1 Brand Generic Preferred Name Name Activity Structure DerivativeZoloft Sertraline Depression

Carbamate Topamax Topiramate Seizures

Carbamate Cymbalta Duloxetine Depression

Carbamate Imitrex Sumatriptan Migraine

Carbamate Lyrica Pregabalin Neuropathic pain

Carbamate or Ester Lamictal Lamotrigine Seizures

Carbamate Valtrex Valaciclovir Herpes

Carbamate Tarceva Erlotinib Non-small cell lung cancer

Carbamate Flomax Tamsulosin Benign prostatic cancer

Carbamate Gleevec Imatinib Leukemia

Carbamate Combivir Zidovudine HIV infection

Carbamate Combivir Lamivudine HIV infection

Carbamate Sustiva Efavirenz HIV infection

Carbamate Epzicom Abacavir HIV infection

Carbamate Kaletra Lopinavir HIV infection

Carbamate Actos Pioglitazone Type-2 diabetes

Carbamate Clarinex Desloratidine Allergic rhinitis

Carbamate Zyrtec Cetirizine Allergic

Ester Protonix Pentoprazole Gastrointestinal

Carbamate Prevacid Lansoprazole Gastrointestinal

Carbamate Aciphex Rebeprazole Gastrointestinal

Carbamate Diovan Valsartan Hypertension

Carbamate Cozaar Losartan Hypertension

Carbamate Avelox Moxifloxacin Bacterial infection

Carbamate or Ester Mobic Meloxicam Osteoarthritis

Carbamate Truspot Dorzolamide Intraocular pressure

Carbamate Voltaren Diclofenac Osteoarthritis & rheumatoid arthritis

Carbamate or Ester Vasotec Enlapril Hypertension

Carbamate or Ester Singulair Montelukast Asthma

Ester Amlodin Amlodipine Hypertension

Carbamate Toporol Metoprolol Hypertension

Carbamate Viagra Sildenafil Erectile dysfunction

Carbamate Coreg Carvedilol Hypertension

Carbamate Delix Ramipril Hypertension

Carbamate or Ester Sinemet (Parcopa, Atamet) L-DOPA Neurologicaldisorders

The purity of the monoterpene (or sesquiterpene) derivatives, or thederivatives of an isomer or analog of monoterpene or sesquiterpene, maybe assayed by gas chromatography (GC) or high pressure liquidchromatography (HPLC). Other techniques for assaying the purity of thecompounds of the present invention and for determining the presence ofimpurities include, but are not limited to, nuclear magnetic resonance(NMR) spectroscopy, mass spectrometry (MS), GC-MS, infrared spectroscopy(IR), and thin layer chromatography (TLC). Chiral purity can be assessedby chiral GC or measurement of optical rotation.

The present compounds may be purified by methods such ascrystallization, or by separating the monoterpene (or sesquiterpene)derivative from impurities according to the unique physicochemicalproperties (e.g., solubility or polarity) of the derivative, or byseparating the isomer or analog of monoterpene or sesquiterpene (or itsderivative), from impurities according to the unique physicochemicalproperties (e.g., solubility or polarity) of the isomer or analog ofmonoterpene or sesquiterpene (or its derivative). Accordingly, themonoterpene (or sesquiterpene) derivative, or the derivative of anisomer or analog of monoterpene or sesquiterpene can be separated bysuitable separation techniques known in the art, such as preparativechromatography, (fractional) distillation, or (fractional)crystallization.

The invention also provides for methods of using monoterpenes (orsesquiterpenes) derivatives, and/or using a derivative of an isomer oranalog of monoterpene or sesquiterpene, to treat a disease, such ascancer or other nervous system disorders. The compounds of the presentinvention may be administered alone, or in combination with radiation,surgery or chemotherapeutic agents. The present compound may beco-administered with antiviral agents, anti-inflammatory agents orantibiotics. The agents may be administered concurrently orsequentially. The present compounds can be administered before, duringor after the administration of the other active agent(s).

The compounds and methods of the present invention may be used toinhibit the Ras protein. The Ras family is a protein family of smallGTPases that are involved in cellular signal transduction. Activation ofRas signaling causes cell growth, differentiation and survival.Mutations in ras genes can permanently activate it and causeinappropriate transmission inside the cell even in the absence ofextracellular signals. Because these signals result in cell growth anddivision, dysregulated Ras signaling can ultimately lead to oncogenesisand cancer. Activating mutations in Ras are found in 20-25% of all humantumors and up to 90% in specific tumor types. Goodsell D S (1999).Downward J., “The molecular perspective: the ras oncogene”. Oncologist 4(3): 263-4. (January 2003). “Targeting RAS signalling pathways in cancertherapy”. Nat. Rev. Cancer 3 (1): 11-22. Ras family members include, butare not limited to, HRAS; KRAS; NRAS; DIRAS1; DIRAS2; DIRAS3; ERAS; GEM;MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B;RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1;REM2; RERG; RERGL; RRAD; RRAS; and RRAS. Wennerberg K, Rossman K L, DerC J (March 2005). “The Ras superfamily at a glance”. J. Cell. Sci. 118(Pt 5): 843-6.

The present compound may be used in combination with radiation therapy.In one embodiment, the present invention provides for a method oftreating tumor cells, such as malignant glioma cells, with radiation,where the cells are treated with an effective amount of a monoterpenederivative, such as a perillyl alcohol ester, and then exposed toradiation. In one embodiment, the present invention provides for amethod of treating tumor cells, such as malignant glioma cells, withradiation, where the cells are treated with an effective amount of aderivative of an isomer or analog of monoterpene or sesquiterpene, suchas an isoperillyl alcohol ester, and then exposed to radiation.Treatment by the compounds of the present invention may be before,during and/or after radiation. For example, the compounds of the presentinvention may be administered continuously beginning one week prior tothe initiation of radiotherapy and continued for two weeks after thecompletion of radiotherapy. U.S. Pat. Nos. 5,587,402 and 5,602,184.

In one embodiment, the present invention provides for a method oftreating tumor cells, such as malignant glioma cells, with chemotherapy,where the cells are treated with an effective amount of a monoterpenederivative, such as a perillyl alcohol ester, and then exposed tochemotherapy. In one embodiment, the present invention provides for amethod of treating tumor cells, such as malignant glioma cells, withchemotherapy, where the cells are treated with an effective amount of aderivative of the isomer or analog of monoterpene or sesquiterpene, suchas an isoperillyl alcohol ester, and then exposed to chemotherapy.Treatment by the present compounds may be before, during and/or afterchemotherapy.

The present compounds may be used for the treatment of nervous systemcancers, such as a malignant glioma (e.g., astrocytoma, anaplasticastrocytoma, glioblastoma multiforme), retinoblastoma, pilocyticastrocytomas (grade I), meningiomas, metastatic brain tumors,neuroblastoma, pituitary adenomas, skull base meningiomas, and skullbase cancer. As used herein, the term “nervous system tumors” refers toa condition in which a subject has a malignant proliferation of nervoussystem cells.

Cancers that can be treated by the present compounds include, but arenot limited to, lung cancer, ear, nose and throat cancer, leukemia,colon cancer, melanoma, pancreatic cancer, mammary cancer, prostatecancer, breast cancer, hematopoietic cancer, ovarian cancer, basal cellcarcinoma, biliary tract cancer; bladder cancer, bone cancer; breastcancer; cervical cancer, choriocarcinoma; colon and rectum cancer,connective tissue cancer; cancer of the digestive system; endometrialcancer; esophageal cancer; eye cancer; cancer of the head and neck;gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx cancer;leukemia including acute myeloid leukemia, acute lymphoid leukemia,chronic myeloid leukemia, chronic lymphoid leukemia; liver cancer;lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; myeloma;fibroma, neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth,and pharynx); ovarian cancer, pancreatic cancer; prostate cancer;retinoblastoma; rhabdomyosarcoma; rectal cancer; renal cancer; cancer ofthe respiratory system; sarcoma; skin cancer, stomach cancer; testicularcancer; thyroid cancer; uterine cancer; cancer of the urinary system, aswell as other carcinomas and sarcomas. U.S. Pat. No. 7,601,355.

The present invention also provides methods of treating CNS disorders,including, without limitation, primary degenerative neurologicaldisorders such as Alzheimer's, Parkinson's, psychological disorders,psychosis and depression. Autism may also be treated by the presentcompositions and methods. Treatment may consist of the use of a compoundof the present invention alone or in combination with currentmedications used in the treatment of Parkinson's, Alzheimer's, orpsychological disorders.

The present invention also provides a method of improvingimmunomodulatory therapy responses comprising the steps of exposingcells to an effective amount of a compound of the present invention,before or during immunomodulatory treatment. Preferred immunomodulatoryagents are cytokines, such interleukins, lymphokines, monokines,interfereons and chemokines.

The present composition may be administered by any method known in theart, including, without limitation, intranasal, oral, transdermal,ocular, intraperitoneal, inhalation, intravenous, ICV, intracisternalinjection or infusion, subcutaneous, implant, vaginal, sublingual,urethral (e.g., urethral suppository), subcutaneous, intramuscular,intravenous, rectal, sub-lingual, mucosal, ophthalmic, spinal,intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchialand lymphatic administration. Topical formulation may be in the form ofgel, ointment, cream, aerosol, etc; intranasal formulation can bedelivered as a spray or in a drop; transdermal formulation may beadministered via a transdermal patch or iontorphoresis; inhalationformulation can be delivered using a nebulizer or similar device.Compositions can also take the form of tablets, pills, capsules,semisolids, powders, sustained release formulations, solutions,suspensions, elixirs, aerosols, or any other appropriate compositions.

To prepare such pharmaceutical compositions, one or more of compound ofthe present invention may be mixed with a pharmaceutical acceptablecarrier, adjuvant and/or excipient, according to conventionalpharmaceutical compounding techniques. Pharmaceutically acceptablecarriers that can be used in the present compositions encompass any ofthe standard pharmaceutical carriers, such as a phosphate bufferedsaline solution, water, and emulsions, such as an oil/water or water/oilemulsion, and various types of wetting agents. The compositions canadditionally contain solid pharmaceutical excipients such as starch,cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, magnesium stearate, sodium stearate, glycerolmonostearate, sodium chloride, dried skim milk and the like. Liquid andsemisolid excipients may be selected from glycerol, propylene glycol,water, ethanol and various oils, including those of petroleum, animal,vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineraloil, sesame oil, etc. Liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols. Forexamples of carriers, stabilizers and adjuvants, see Remington'sPharmaceutical Sciences, edited by E. W. Martin (Mack PublishingCompany, 18th ed., 1990). The compositions also can include stabilizersand preservatives.

As used herein, the term “therapeutically effective amount” is an amountsufficient to treat a specified disorder or disease or alternatively toobtain a pharmacological response treating a disorder or disease.Methods of determining the most effective means and dosage ofadministration can vary with the composition used for therapy, thepurpose of the therapy, the target cell being treated, and the subjectbeing treated. Treatment dosages generally may be titrated to optimizesafety and efficacy. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician. Suitable dosage formulations and methods of administering theagents can be readily determined by those of skill in the art. Forexample, the composition are administered at about 0.01 mg/kg to about200 mg/kg, about 0.1 mg/kg to about 100 mg/kg, or about 0.5 mg/kg toabout 50 mg/kg. When the compounds described herein are co-administeredwith another agent or therapy, the effective amount may be less thanwhen the agent is used alone.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer. If thecomposition is in the form of a gel, the composition may be rubbed ontoa membrane of the patient, for example, the skin, preferably intact,clean, and dry skin, of the shoulder or upper arm and or the uppertorso, and maintained thereon for a period of time sufficient fordelivery of the present compound to the blood serum of the patient. Thecomposition of the present invention in gel form may be contained in atube, a sachet, or a metered pump. Such a tube or sachet may contain oneunit dose, or more than one unit dose, of the composition. A meteredpump may be capable of dispensing one metered dose of the composition.

This invention also provides the compositions as described above forintranasal administration. As such, the compositions can furthercomprise a permeation enhancer. Southall et al. Develonments in NasalDrug Deliver, 2000. The present compound may be administeredintranasally in a liquid form such as a solution, an emulsion, asuspension, drops, or in a solid form such as a powder, gel, orointment.

Devices to deliver intranasal medications are well known in the art.Nasal drug delivery can be carried out using devices including, but notlimited to, intranasal inhalers, intranasal spray devices, atomizers,nasal spray bottles, unit dose containers, pumps, droppers, squeezebottles, nebulizers, metered dose inhalers (MDI), pressurized doseinhalers, insufflators, and bi-directional devices. The nasal deliverydevice can be metered to administer an accurate effective dosage amountto the nasal cavity. The nasal delivery device can be for single unitdelivery or multiple unit delivery. In a specific example, the ViaNaseElectronic Atomizer from Kurve Technology (Bethell, Washington) can beused in this invention (http://www.kurvetech.com). The compounds of thepresent invention may also be delivered through a tube, a catheter, asyringe, a packtail, a pledget, a nasal tampon or by submucosalinfusion. U.S. Patent Publication Nos. 20090326275, 20090291894,20090281522 and 20090317377.

The present compound can be formulated as aerosols using standardprocedures. The compound may be formulated with or without solvents, andformulated with or without carriers. The formulation may be a solution,or may be an aqueous emulsion with one or more surfactants. For example,an aerosol spray may be generated from pressurized container with asuitable propellant such as, dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, hydrocarbons,compressed air, nitrogen, carbon dioxide, or other suitable gas. Thedosage unit can be determined by providing a valve to deliver a meteredamount. Pump spray dispensers can dispense a metered dose or a dosehaving a specific particle or droplet size. As used herein, the term“aerosol” refers to a suspension of fine solid particles or liquidsolution droplets in a gas. Specifically, aerosol includes a gas-bornesuspension of droplets of a monoterpene (or sesquiterpene), as may beproduced in any suitable device, such as an MDI, a nebulizer, or a mistsprayer. Aerosol also includes a dry powder composition of thecomposition of the instant invention suspended in air or other carriergas. Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems6:273-313. Raeburn et al., (1992) Pharmacol. Toxicol. Methods27:143-159.

The present compound may be delivered to the nasal cavity as a powder ina form such as microspheres delivered by a nasal insufflator. Thepresent compound may be absorbed to a solid surface, for example, acarrier. The powder or microspheres may be administered in a dry,air-dispensable form. The powder or microspheres may be stored in acontainer of the insufflator. Alternatively the powder or microspheresmay be filled into a capsule, such as a gelatin capsule, or other singledose unit adapted for nasal administration.

The pharmaceutical composition can be delivered to the nasal cavity bydirect placement of the composition in the nasal cavity, for example, inthe form of a gel. an ointment, a nasal emulsion, a lotion, a cream, anasal tampon, a dropper, or a bioadhesive strip. In certain embodiments,it can be desirable to prolong the residence time of the pharmaceuticalcomposition in the nasal cavity, for example, to enhance absorption.Thus, the pharmaceutical composition can optionally be formulated with abioadhesive polymer, a gum (e.g., xanthan gum), chitosan (e.g., highlypurified cationic polysaccharide), pectin (or any carbohydrate thatthickens like a gel or emulsifies when applied to nasal mucosa), amicrosphere (e.g., starch, albumin, dextran, cyclodextrin), gelatin, aliposome, carbamer, polyvinyl alcohol, alginate, acacia, chitosansand/or cellulose (e.g., methyl or propyl; hydroxyl or carboxy;carboxymethyl or hydroxylpropyl).

The composition containing the present compound can be administered byoral inhalation into the respiratory tract, i.e., the lungs.

Typical delivery systems for inhalable agents include nebulizerinhalers, dry powder inhalers (DPI), and metered-dose inhalers (MDI).

Nebulizer devices produce a stream of high velocity air that causes atherapeutic agent in the form of liquid to spray as a mist. Thetherapeutic agent is formulated in a liquid form such as a solution or asuspension of particles of suitable size. In one embodiment, theparticles are micronized. The term “micronized” is defined as havingabout 90% or more of the particles with a diameter of less than about 10μm. Suitable nebulizer devices are provided commercially, for example,by PARI GmbH (Starnberg, Germany). Other nebulizer devices includeRespimat (Boehringer Ingelheim) and those disclosed in, for example,U.S. Pat. Nos. 7,568,480 and 6,123,068, and WO 97/12687. The presentcompound can be formulated for use in a nebulizer device as an aqueoussolution or as a liquid suspension.

DPI devices typically administer a therapeutic agent in the form of afree flowing powder that can be dispersed in a patient's air-streamduring inspiration. DPI devices which use an external energy source mayalso be used in the present invention. In order to achieve a freeflowing powder, the present compound can be formulated with a suitableexcipient (e.g., lactose). A dry powder formulation can be made, forexample, by combining dry lactose having a particle size between about 1μm and 100 μm with micronized particles of the present compound and dryblending. Alternatively, the compound can be formulated withoutexcipients. The formulation is loaded into a dry powder dispenser, orinto inhalation cartridges or capsules for use with a dry powderdelivery device. Examples of DPI devices provided commercially includeDiskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g.,U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline) (see, e.g., U.S. Pat.No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Del.) (see, e.g.,U.S. Pat. No. 4,524,769); and Rotahaler (GlaxoSmithKline) (see, e.g.,U.S. Pat. No. 4,353,365). Further examples of suitable DPI devices aredescribed in U.S. Pat. Nos. 5,415,162, 5,239,993, and 5,715,810 andreferences therein.

MDI devices typically discharge a measured amount of the storedcomposition using compressed propellant gas. Formulations for MDIadministration include a solution or suspension of an active ingredientin a liquefied propellant. Examples of propellants includehydrofluoroalklanes (HFA), such as 1,1,2-tetrafluoroethane (HFA 134a)and 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA 227), andchlorofluorocarbons, such as CCl₃F. Additional components of HFAformulations for MDI administration include co-solvents, such asethanol, pentane, water; and surfactants, such as sorbitan trioleate,oleic acid, lecithin, and glycerin. (See, for example, U.S. Pat. No.5,225,183, EP 0717987, and WO 92/22286). The formulation is loaded intoan aerosol canister, which forms a portion of an MDI device. Examples ofMDI devices developed specifically for use with HFA propellants areprovided in U.S. Pat. Nos. 6,006,745 and 6,143,227. For examples ofprocesses of preparing suitable formulations and devices suitable forinhalation dosing see U.S. Pat. Nos. 6,268,533, 5,983,956, 5,874,063,and 6,221,398, and WO 99/53901, WO 00/61108, WO 99/55319 and WO00/30614.

The present compound may be encapsulated in liposomes or microcapsulesfor delivery via inhalation. A liposome is a vesicle composed of a lipidbilayer membrane and an aqueous interior. The lipid membrane may be madeof phospholipids, examples of which include phosphatidylcholine such aslecithin and lysolecithin; acidic phospholipids such asphosphatidylserine and phosphatidylglycerol; and sphingophospholipidssuch as phosphatidylethanolamine and sphingomyelin. Alternatively,cholesterol may be added. A microcapsule is a particle coated with acoating material. For example, the coating material may consist of amixture of a film-forming polymer, a hydrophobic plasticizer, a surfaceactivating agent or/and a lubricant nitrogen-containing polymer. U.S.Pat. Nos. 6,313,176 and 7,563,768.

The present compound may also be used alone or in combination with otherchemotherapeutic agents via topical application for the treatment oflocalized cancers such as breast cancer or melanomas. The presentcompound may also be used in combination with narcotics or analgesicsfor transdermal delivery of pain medication.

This invention also provides the compositions as described above forocular administration. As such, the compositions can further comprise apermeation enhancer. For ocular administration, the compositionsdescribed herein can be formulated as a solution, emulsion, suspension,etc. A variety of vehicles suitable for administering compounds to theeye are known in the art. Specific non-limiting examples are describedin U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445;5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851.

The present compound can be given alone or in combination with otherdrugs for the treatment of the above diseases for a short or prolongedperiod of time. The present compositions can be administered to amammal, preferably a human. Mammals include, but are not limited to,murines, rats, rabbit, simians, bovines, ovine, porcine, canines,feline, farm animals, sport animals, pets, equine, and primates.

The invention also provides a method for inhibiting the growth of a cellin vitro, ex vivo or in vivo, where a cell, such as a cancer cell, iscontacted with an effective amount of the present compound as describedherein.

Pathological cells or tissue such as hyperproliferative cells or tissuemay be treated by contacting the cells or tissue with an effectiveamount of a composition of this invention. The cells, such as cancercells, can be primary cancer cells or can be cultured cells availablefrom tissue banks such as the American Type Culture Collection (ATCC).The pathological cells can be cells of a systemic cancer, gliomas,meningiomas, pituitary adenomas, or a CNS metastasis from a systemiccancer, lung cancer, prostate cancer, breast cancer, hematopoieticcancer or ovarian cancer. The cells can be from a vertebrate, preferablya mammal, more preferably a human. U.S. Patent Publication No.2004/0087651. Balassiano et al. (2002) Intern. J. Mol. Med. 10:785-788.Thorne, et al. (2004) Neuroscience 127:481-496. Fernandes, et al. (2005)Oncology Reports 13:943-947. Da Fonseca, et al. (2008) Surical Neurology70:259267. Da Fonseca, et al. (2008) Arch. Immunol. Ther. Exp.,56:267-276. Hashizume, et al. (2008) Neuroncolov 10:112-120.

In vitro efficacy of the present composition can be determined usingmethods well known in the art. For example, the cytoxicity of thepresent compound may be studied by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide]cytotoxicity assay. MTT assay is based on the principle of uptake ofMTT, a tetrazolium salt, by metabolically active cells where it ismetabolized into a blue colored formazon product, which can be readspectrometrically. J. of Immunological Methods 65: 55 63, 1983. Thecytoxicity of the present compound may be studied by colony formationassay. Functional assays for inhibition of VEGF secretion and IL-8secretion may be performed via ELISA. Cell cycle block by the presentcompound may be studied by standard propidium iodide (PI) staining andflow cytometry. Invasion inhibition may be studied by Boyden chambers.In this assay a layer of reconstituted basement membrane, Matrigel, iscoated onto chemotaxis filters and acts as a barrier to the migration ofcells in the Boyden chambers. Only cells with invasive capacity cancross the Matrigel barrier. Other assays include, but are not limitedto, cell viability assays, apoptosis assays, and morphological assays.

The following are examples of the present invention and are not to beconstrued as limiting.

EXAMPLES Example 1: Synthesis of 2-Propyl pentanoic acid 4-isopropenylcyclohex-1-enylmethyl ester (POH-Valproate Conjugate)

The reaction scheme is as follows.

Experimental Procedure for the Synthesis of 2-Propyl pentanoic acid4-isopropenyl cyclohex-1-enylmethyl ester (POH-Valproate)

Thionly chloride (39.6 g, 332 mmol) was added slowly to Valproic acid(1, 16.0 g, 110 mmol) while maintaining the internal temperature at 10°C. The resulting mixture was allowed to warm to room temperature (RT)and stirred for about 4.0 hours. The excess thionyl chloride wasrecovered by concentration under vacuum to obtain the Valproyl chloride(2) as a pale yellow liquid (16.8 g, Yield: 94%).

Valproyl chloride (2, 11.08 g, 68.14 mmol) was added slowly to a mixtureof Perillyl alcohol (POH 3, 8.0 g, 52.55 mmol), Triethylamine (8.5 g, 84mmol), and dichloromethane (80 mL) while maintaining the temperaturebetween 10-15° C. The mixture was stirred for 2.0 hours at RT and thenquenched with water (40 mL). The separated organic layer was washedsequentially with sodium bicarbonate (5%, 40 mL), water (40 mL), andbrine (5%, 40 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated under vacuum to obtain the crudePOH-Valproate as an orange liquid which was then purified on a Thomsonsingle StEP column (50 g) and eluting with hexanes followed by 2.0%ethyl acetate/hexanes. The purified 2.0% ethyl acetate/hexanes fractionswere combined and concentrated under vacuum to give POH-Valproate (4) asa colorless liquid (purity greater than about 95%). Weight: 12.14 g;Yield: 83%. ¹H-NMR (400 MHz, CDCl₃): δ 0.89 (t, 6H), 1.30 (m, 4H),1.38-1.53 (m, 31-), 1.57-1.65 (m, 2H), 1.74 (s, 3H), 1.82-1.90 (m, 1H),1.94-2.30 (m, 1H), 2.04-2.20 (m, 4H), 2.34-2.42 (m, 1H), 4.46 (q, 2H),4.72 (dd, 2H), 5.77 (s, 1H). MS (APCI method): m/e: 279 (M⁺¹ 100%), 269(60%), 261 (27%).

Example 2: Synthesis of 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester (IsoPOH-ValproateConjugate)

The reaction scheme is as follows.

Experimental Procedure for the Synthesis of 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester (isoPOH-Valproate)

Thionly chloride (39.6 g, 332 mmol) was added slowly to Valproic acid(1, 16.0 g, 110 mmol) while maintaining the internal temperature at 10°C. The resulting mixture was allowed to warm to room temperature (RT)and stirred for about 4.0 hours. The excess thionyl chloride was removedby concentration under vacuum to obtain the Valproyl chloride (2) as apale yellow liquid (16.8 g, Yield: 94%).

Valproyl chloride (2, 11.08 g, 68.14 mmol) will be added slowly to amixture of Isoperillyl alcohol (IsoPOH 3, 8.0 g, 52.55 mmol),Triethylamine (8.5 g, 84 mmol), and dichloromethane (80 mL) whilemaintaining the temperature between 10-15° C. The mixture will bestirred for 2.0 hours at RT and then will be quenched with water (40mL). The separated organic layer will be washed sequentially with sodiumbicarbonate (5%, 40 mL), water (40 mL), and brine (5%, 40 mL). Theorganic layer will be dried over sodium sulfate, filtered, andconcentrated under vacuum to obtain the crude IsoPOH-Valproate as aliquid which will be purified on a Thomson single StEP column (50 g) andwill be eluted with hexanes followed by 2.0% ethyl acetate/hexanes. Thepurified 2.0% ethyl acetate/hexanes fractions will be combined andconcentrated under vacuum to obtain pure IsoPOH-Valproate (4) as acolorless liquid.

The scope of the present invention is not limited by what has beenspecifically shown and described hereinabove. Those skilled in the artwill recognize that there are suitable alternatives to the depictedexamples of materials, configurations, constructions and dimensions.Numerous references, including patents and various publications, arecited and discussed in the description of this invention. The citationand discussion of such references is provided merely to clarify thedescription of the present invention and is not an admission that anyreference is prior art to the invention described herein. All referencescited and discussed in this specification are incorporated herein byreference in their entirety. Variations, modifications and otherimplementations of what is described herein will occur to those ofordinary skill in the art without departing from the spirit and scope ofthe invention. While certain embodiments of the present invention havebeen shown and described, it will be obvious to those skilled in the artthat changes and modifications may be made without departing from thespirit and scope of the invention. The matter set forth in the foregoingdescription and accompanying drawings is offered by way of illustrationonly and not as a limitation.

What is claimed is:
 1. A pharmaceutical composition comprising aperillyl alcohol conjugated with valproic acid.
 2. The pharmaceuticalcomposition of claim 1, wherein the perillyl alcohol conjugated withvalproic acid is an ester of perillyl alcohol with valproic acid.
 3. Thepharmaceutical composition of claim 2, wherein the ester is2-Propylpentanoic acid 4-isopropenyl-cyclohex-1-enylmethyl ester.
 4. Thepharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition is administered by inhalation, intranasally, orally,intravenously, subcutaneously or intramuscularly.
 5. The pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition isadmixed or coformulated with a therapeutic agent.
 6. A pharmaceuticalcomposition comprising an isoperillyl alcohol conjugated with valproicacid.
 7. The pharmaceutical composition of claim 6, wherein theisoperillyl alcohol conjugated with valproic acid is an ester ofisoperillyl alcohol with valproic acid.
 8. The pharmaceuticalcomposition of claim 7, wherein the ester is 2-Propyl-pentanoic acid4-isopropylidene-cyclohex-1-enylmethyl ester.
 9. The pharmaceuticalcomposition of claim 6, wherein the isoperillyl alcohol is selected fromthe group consisting of (4-isopropylidene cyclohex-1-enyl)methanol,(4-isopropyl cyclohexa-1,3-dienyl)methanol, (4-isopropylcyclohexa-1,4-dienyl)methanol, (4-isopropylphenyl)methanol and(4-isopropenylphenyl)methanol.
 10. The pharmaceutical composition ofclaim 6, wherein the pharmaceutical composition is administered byinhalation, intranasally, orally, intravenously, subcutaneously orintramuscularly.
 11. The pharmaceutical composition of claim 6, whereinthe pharmaceutical composition is admixed or coformulated with atherapeutic agent.
 12. A pharmaceutical composition comprising atherapeutically effective amount of 2-Propylpentanoic acid4-isopropenyl-cyclohex-1-enylmethyl ester.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of2-Propyl-pentanoic acid 4-isopropylidene-cyclohex-1-enylmethyl ester.14. A method for treating a disease in a mammal, comprising the step ofadministering to the mammal a therapeutically effective amount of aperillyl alcohol conjugated with valproic acid.
 15. The method of claim14, wherein the perillyl alcohol conjugated with vaiproic acid is anester of perillyl alcohol with valproic acid.
 16. The method of claim15, wherein the ester is 2-Propylpentanoic acid4-isopropenyl-cyclohex-1-enylmethyl ester.
 17. The method of claim 14,wherein the disease is cancer.
 18. The method of claim 17, wherein thecancer is a tumor of the nervous system.
 19. The method of claim 18,wherein the tumor is a glioblastoma.
 20. The method of claim 14, furthercomprising the step of treating the mammal with radiation.
 21. Themethod of claim 14, further comprising the step of administering to themammal a chemotherapeutic agent.
 22. The method of claim 14, wherein theperillyl alcohol conjugated with valproic acid is administered byinhalation, intranasally, orally, intravenously, subcutaneously orintramuscularly.
 23. A method for treating a disease in a mammal,comprising the step of administering to the mammal a therapeuticallyeffective amount of an isoperillyl alcohol conjugated with valproicacid.
 24. The method of claim 23, wherein the isoperillyl alcoholconjugated with valproic acid is an ester of isoperillyl alcohol withvalproic acid.
 25. The method of claim 24, wherein the ester is2-Propyl-pentanoic acid 4-isopropylidene-cyclohex-1-enylmethyl ester.26. The method of claim 23, wherein the disease is cancer.
 27. Themethod of claim 26, wherein the cancer is a tumor of the nervous system.28. The method of claim 27, wherein the tumor is a glioblastoma.
 29. Themethod of claim 23, further comprising the step of treating the mammalwith radiation.
 30. The method of claim 23, further comprising the stepof administering to the mammal a chemotherapeutic agent.
 31. The methodof claim 23, wherein the isoperillyl alcohol conjugated with valproicacid is administered by inhalation, intranasally, orally, intravenously,subcutaneously or intramuscularly.
 32. A method for treating a diseasein a mammal, comprising the step of administering to the mammal atherapeutically effective amount of a perillyl alcohol conjugated withvalproic acid or an isoperillyl alcohol conjugated with valproic acidusing a nasal delivery device.
 33. The method of claim 32, wherein thenasal delivery device is selected from the group consisting of anintranasal inhaler, an intranasal spray device, an atomizer, anebulizer, a metered dose inhaler (MDI), a pressurized dose inhaler, aninsufflator, a unit dose container, a pump, a dropper, a squeeze bottleand a bi-directional device.